Layered sensor for determining an analyte concentration

ABSTRACT

An implantable sensor is provide which can be used for determining a concentration of at least one analyte in a medium, in particular a body tissue and/or a body fluid. The implantable sensor has a layered construction with at least one insulating carrier substrate and at least two electrodes which are arranged in at least two different layer planes of the implantable sensor and are electrically isolated from one another by the at least one insulating carrier substrate. The electrodes have electrode areas which face the medium when the sensor has been implanted, and are in contact with the medium over a large area and substantially uniformly, directly or via a generally analyte-permeable membrane layer.

CLAIM OF PRIORITY

The present application is a continuation application based on andclaiming priority to PCT Application Filing, No. PCT/EP2006/069386,filed Dec. 6, 2006, which claims the priority benefit of GermanApplication Filing No. DE 10 2006 041 343.1, filed Sep. 1, 2006, whichclaims the priority benefit of European Application Filing No. EP 05 027755.7, filed Dec. 19, 2005, each of which applications are herebyincorporated by reference in their entireties.

TECHNICAL FIELD OF THE INVENTION

The present application relates to an implantable sensor for determininga concentration of at least one analyte in a sample, such as a bodytissue or body fluid, to a device using such an implantable sensor, to amethod of using such an implantable sensor and/or the device, and to amethod for producing the implantable sensor; and more particularly tosuch sensors, devices and methods in the field of medical technology,and more particularly to electrochemical determination of theconcentration of blood glucose, triglycerides, lactate, or other bloodanalytes.

BACKGROUND

For diabetics, determining the blood glucose concentrations andcorresponding medication are an essential part of the course of the day.In this case, the blood glucose concentration has to be determinedrapidly and simply a number of times a day (typically two to seventimes) in order to be able to take corresponding medical measures, ifappropriate. In many cases, medication is effected by means of automaticsystems, in particular so-called insulin pumps.

In order not to restrict the diabetic's day any more than necessary,correspondingly mobile devices are often used, which should be simple totransport and handle, so that the blood glucose concentration can bemeasured without any problems, for example at the workplace or elseduring leisure time. Various mobile devices which function in partaccording to different measurement methods and using different diagnosismethods are commercially available at the present time. A firstmeasurement method is based on an electrochemical measurement method.For example, a blood sample, taken from the body tissue from the patientfor example by perforating a skin layer by means of a lancet, is appliedto an electrode coated with enzymes and mediators. Corresponding teststrips for electrochemical measurement methods of this type aredescribed in U.S. Pat. No. 5,286,362, for example, the disclosure ofwhich is hereby incorporated herein by reference. Other knownmeasurement methods use optical measurement methods based for example onthe fact that the substance (analyte) to be detected may react withspecific detection reagents, a change in the color of the reactionmixture occurring. Systems for detecting such color reactions and thusfor detecting the corresponding analytes are known from CA 2,050,677,for example, the disclosure of which is hereby incorporated herein byreference.

The detection methods described are therefore based predominantly on thefact that a patient firstly takes a corresponding sample of the bodyfluid to be examined (this being for example a blood sample or a urinesample) and then examines it correspondingly by means of the testdevice. However, this method comprises various disadvantages. Firstly,this method is extremely complicated and presupposes a plurality ofhandling steps. Thus, by way of example, a lancet has to be provided andtensioned, a skin layer subsequently has to be perforated by means ofsaid lancet, a drop of blood thus produced then has to be applied to atest strip, and said test strip subsequently has to be evaluated bymeans of a corresponding device. For many patients, in particular olderpeople and children, these handling steps can often be carried out onlywith difficulty since the patients are restricted for example in termsof their motor ability and their vision capability. Furthermore, thesemethod steps can be carried out discretely only in a few cases, suchthat for example protection of the patient's privacy during ameasurement at the workplace is only inadequately ensured. Moreover,incorrect operation of the measurement method can easily lead to falsemeasured values, with in some instances fatal consequences of anincorrect medication based on the measurement results.

The prior art therefore discloses systems which can be implanted into abody tissue and which supply measured values continuously. See, forexample, U.S. Pat. No. 6,892,085 and U.S. Pat. No. 5,591,139, thedisclosures of which are hereby incorporated herein by reference intheir entireties.

Overall, however, the implantable sensors known from the prior art areextremely complicated with regard to their construction and theirproduction. If it is assumed that said sensors are disposable sensorsthat can only be used for a short time (typically approximately oneweek), then it becomes clear that the complicated manufacturing methodsused for making the sensors: known from the prior art do not satisfysuch requirements made of disposable articles. See, for example, thelithographic methods disclosed by U.S. Pat. No. 5,591,139 and U.S. Pat.No. 6,892,085 which are referenced supra. However, such methods cannotbe reconciled with the production of cost-effective disposable articles.

Moreover, lithographic methods, in particular the etching of metallayers that is associated with these methods, are not always as reliableas necessary for producing medical-technological products. Inparticular, it can happen that individual electrodes are still connectedto one another by “bridges”, such that the functionality of the sensorscan easily be impaired or even completely prevented on account ofproduction problems. A further disadvantage of the sensors known fromthe prior art, such as, for example, the sensors known from U.S. Pat.No. 6,892,085 B2 and U.S. Pat. No. 5,591,139, furthermore arises in theuse of a hollow needle or capillary. In these cases, the sensors areintroduced into a capillary which transports the body fluid to beexamined towards the sensor. What is disadvantageous about this,however, is that the capillary makes it more difficult for the analytesolution to have unimpeded access to the electrodes. In particular, thiscan also give rise to local concentration corruptions which have theeffect that measurement results do not correspond to the actualconcentration conditions in the body fluid. In this case, complexdiffusion processes and flow processes in the capillaries also play apart and contribute to the corruption.

Other prior art sensors are provided for in vivo measurement based on anelectrochemical principle, having two electrodes on a carrier substrate.See, for example, US 2004/0111017, the disclosure of which is herebyincorporated by reference in its entirety. In such in vivo sensors, aworking electrode coated with a detector layer for the analyte to, bedetected is applied directly to the carrier substrate and covered by acovering layer. A common reference electrode and counter electrode canbe applied on the opposite side of the covering layer to the workingelectrode and overlaps the working electrode but is isolated from thelatter by the covering layer (which is necessarily to be configured inelectrically insulating fashion). The analyte passes via diffusionmechanisms from the edges of the sensor to the working electrode. As analternative, the covering layer itself can also be madeanalyte-permeable.

Such a sensor arrangement has various disadvantages in practice,however. One exemplary disadvantage is the fact that the covering layermust simultaneously perform two different functions which are compatibleonly with difficulty in terms of material technology. Thus, the coveringlayer must on the one hand have sufficient electrically insulatingproperties in order to insulate the working electrode and the counterelectrode from one another. The covering layer must nevertheless enablethe analyte that is to be detected to penetrate at least from the edgein order to pass to the working electrode, in order to be able to bedetected electrochemically there. This diffusion must able to take placeto a sufficient extent in order to be able to provide sufficientresponsive electrical currents for a measurement of the analyteconcentration (signal response). The simultaneous permeability fordiffusion and sufficient insulation capability make stringentrequirements of the material properties, however. One solution forsolving this problem is a structural configuration of the sensor inwhich diffusion channels enabling the analyte to penetrate are providedin the layer construction. However, this structure is technically socomplicated that the production advantages which can be afforded by alayer construction are virtually completely given away again.

It is an object of the invention, therefore, to provide a sensor fordetermining a concentration of at least one analyte in a medium, whichsensor can be produced simply and cost-effectively by means of areliable production method and if possible avoids the disadvantages ofthe sensors and methods known from the prior art. In particular, thesensor is intended to be implantable and to ensure sufficient signalswings.

SUMMARY

This object and others that will be appreciated by a person of ordinaryskill in the art have been achieved according to the embodiments of thepresent invention disclosed herein. In one embodiment, the presentinvention comprises an implantable sensor for determining aconcentration of at least one analyte in a medium, in particular in abody tissue and/or a body fluid. The analyte may be for example glucose,triglycerides, lactate, hormones or other analytes which are importantparticularly in medicine. As an alternative or in addition, however, thesensor can also be used for measuring other types of analytes. In oneembodiment, the sensor is based on the use of an electrochemicalmeasurement method.

A basic concept of the invention comprises using a suitable layeredconstruction to solve the above-described problem that, on the one hand,electrical insulation of the electrodes from one another is necessaryand, on the other hand, the electrodes should be as freely accessible aspossible for the at least one analyte. Accordingly, an implantablesensor is configured in such a way that at least two electrodes areapplied on an electrically insulating carrier substrate in at least twodifferent layer planes, for example on a front side and a rear sideand/or in different step planes. The at least two electrodes areelectrically isolated from one another by the at least one carriersubstrate.

Furthermore, the at least: two electrodes have electrode areas, that isto say active surfaces, at which electrochemical reactions (redoxreactions) can proceed. According to the invention, in order to obtainthe maximum signal response, these at least two electrode areas face themedium when the sensor has been implanted into the medium, and are incontact with the medium substantially uniformly, directly or via ananalyte-permeable membrane layer. The intention is not only to enableanalyte to penetrate via the sensor edge, but also to enable contact totake place perpendicular to the electrode areas from the medium. Thus,analyte is generally unimpeded to the entire electrode areas.Nevertheless, slight restrictions of accessibility can be accepted here,for example by slight coverings of the electrode areas, for example ofnot more than 10% of the electrode areas.

The configuration according to the invention has therefore separated andthus optimized the two functions which are realized by one and the samelayer, namely the covering layer between the overlapping electrodes. Theelectrical insulation is now realized by the at least one insulatingcarrier substrate and the spatial arrangement of the at least twoelectrodes. The accessibility of the electrodes to the medium or theanalyte is ensured by virtue of the fact that the at least twoelectrodes no longer overlap completely or partially, rather they arearranged for example alongside one another and are freely in contactwith the medium. In this case, as described above, “freely” should beunderstood not to be limited to completely free accessibility butincludes contact via a membrane layer which is generally permeable tothe at least one analyte. An appropriate membrane layer can ensure, forexample, the biocompatibility and thus the implantability of the sensor(see below). Such a membrane layer, which is configured for example toprevent diffusion of electrode material or parts thereof into the medium(e.g. cell tissue), or to provide for contact of the at least oneelectrode with the medium, does not have to satisfy any requirementswhatsoever in terms of the electrical insulation effect. Therefore, aslong as the biocompatibility requirements are met, the membrane layercan be made as thin as desired, for example. Overall, therefore, in thiscase the membrane layer and the at least one carrier substrate togetherperform the tasks which are fulfilled by the covering layer alone, ifappropriate in interaction with the complex diffusion channels.

The implantable sensor can be advantageously developed in various waysaccording to the invention. In this case, the advantageous developmentsdescribed can be used individually or in combination.

In one embodiment, the at least two electrodes comprise at least oneworking electrode and at least one further electrode, such as a counterelectrode and/or a reference electrode. In this case, the at least oneworking electrode and the at least one further electrode are arranged indifferent planes of the layered construction. The analyte concentrationis then measured after wetting by the medium or after implantation ofthe sensor by means of amperometric measurement between the at least twoelectrodes (e.g., working electrode and counter electrode), such as bymeans of a DC voltage. A reference electrode for currentless measurementof the working electrode potential can additionally be used.

In this case, “in different-planes” should be understood to meangenerally that at least one insulating carrier substrate is arrangedbetween the at least two electrodes, such that at least two of the atleast two electrodes are isolated by the insulating carrier substrate.Consequently, in contrast to the prior art described above, the “thirddimension” is concomitantly used in this construction of an implantablesensor.

Although the prior art discloses electrochemical cells, for exampleelectrochemical microcells, in which electrodes are arranged on oppositesides of a carrier, there the carrier is an electrolyte material, inparticular a solid electrolyte. In contrast thereto, the at least oneinsulating carrier substrate of the electrochemical sensor according tothe present invention comprises an electrically non-conductive material.This is intended to mean generally that if a voltage of up toapproximately 1-2 volts is applied to two electrodes arranged onopposite sides of the at least one insulating carrier substrate,currents of not more than one milliampere, preferably of not more than100 microamperes, and particularly preferably of not more than 10microamperes, flow. This generally ensures that the measurement currenton account of the electrochemical measurement method is considerablygreater than the current which flows through the at least one insulatingcarrier substrate despite the insulating properties of the electricallynon-conductive material of the at least one insulating carriersubstrate.

Furthermore, the at least one carrier substrate can also additionally beconfigured in such a way that diffusion of the at least one analytethrough the at least one carrier substrate is not possible or is greatlyimpeded. In this respect, the at least one carrier substrate alsodiffers significantly with regard to the material requirements from thecovering layer used in prior art sensors such that a larger number ofsuitable materials are available and can be used.

For making contact with the at least two electrodes, the embodiments ofan implantable sensor of the present invention can furthermore have oneor a plurality of electrode contact layers. The latter may involve forexample electrically conductive layers, e.g. metallic layers, inparticular layers having carbon, graphite, gold, silver, platinum and/oraluminum. Multilayered constructions are also possible. Organicconductor materials are also appropriate as electrode contact layersthat make electrical contact.

Since the at least two electrodes are arranged in at least two layerplanes of the layer construction of the sensor, it is now possible forthe at least two electrodes and/or the at least two electrode contactlayers to extend substantially over the entire width of the at least oneinsulating carrier substrate. Thus, the insulating carrier substrate mayin particular have a longitudinal extent and also a width and a length,the electrode contact layers and/or the electrodes substantiallyextending from one edge of the insulating carrier substrate to theother. In this case, “substantially” can be understood to mean acovering of the insulating carrier substrate by the electrode contactlayer of at least 80%, and in certain embodiments at least 95% and up to100%. Therefore, on account of the separation by the construction indifferent planes, a structuring of the electrodes and/or electrodecontact layers is no longer necessary, such that complex lithographicstructuring methods or laser structuring methods (e.g. laser ablation)can be dispensed with. The advantages of this possibility will becomeclear below when a possible method for the production of the implantablesensor is described in detail.

Furthermore, the implantable sensor can have at least one insulatorlayer which covers and preferably electrically insulates the at leasttwo electrode contact layers at least partly with respect to the medium,in particular the body tissue and/or the body fluid. In this case, thefor example at least two electrode contact layers can be partly coveredby the at least two electrodes, the uncovered regions being covered(e.g. subsequently) by the at least one insulator layer. Self-adhesivefilm layers can be used as insulator layers. In this way, by way ofexample, the at least one insulator layer prevents undesirableelectrochemical reactions, for example electrolysis reactions with gasformation, from proceeding at the uncovered regions of the electrodecontact layers upon contact with the surrounding medium and applicationof a voltage.

Even further layers not mentioned can also be provided alongside thelayer construction described above. Thus, the at least one insulatingcarrier substrate may initially be a carrier substrate composed of, forexample, a plastic, ceramic or paper material. As an alternative or inaddition, the at least one carrier substrate itself may already have amultilayered construction, for example a substrate material coated withfurther layers. Thus, by way of example, substrate materials withadditional barrier layers can be used. It is particularly preferred ifthe at least one insulating carrier substrate comprises a polymer, suchas an insulating polymer, e.g. a polyester. Further layers, for exampleconductive or electrically insulating layers, can also be introducedbetween the at least one insulating carrier substrates and the at leasttwo electrode contact layers and/or the at least two electrodes.

The implantable sensor in accordance with the embodiments describedherein can be inserted for example into a canula. In one embodiment, theimplantable sensor can be introduced into the medium, in particular thebody tissue, directly, that is to say without a surrounding canula orcapillary. This ensures that body fluid can wash freely around theelectrodes arranged in the at least two planes. For this purpose, theimplantable sensor, as already described above, can have at least onemembrane layer that completely or partly encloses the layerconstruction. Said at least one membrane layer advantageously has, atleast in part, a permeability to the at least one analyte that is to bedetected. By way of example, the at least one membrane layer can have apermeability to glucose, lactate, triglycerides and/or further analytes.In this case, however, the at least one membrane layer shouldadvantageously be impermeable to auxiliary chemicals used in theelectrochemical measurement method, for example to enzymes used whichare applied to one or more of the electrodes. By way of example, glucoseoxidase may be involved in this electrochemical method. Consequently,the membrane layer also ensures that said auxiliary chemicals, which areof considerable toxicity in some instances (e.g. glucose oxidaseconstitutes a cell poison), cannot pass into the body tissue and causedamage there.

The at least one membrane layer can enclose for example the region inwhich the electrodes are applied. By way of example, the at least onemembrane layer can have a polyurethane. A multilayered membrane layerconstruction is also possible. By way of example, wet-chemical methods,e.g. dipping methods or spraying methods, or else other known coatingmethods can be used for applying the polyurethane.

The at least two electrodes can be configured in various ways. Inparticular, the at least two electrodes, as described above, cancomprise at least one working electrode and at least one furtherelectrode having at least one counter electrode and at least onereference electrode. In particular, the at least one counter electrodeshould have an Opposite redox behavior to a redox behavior of the atleast one working electrode. A counter electrode and a referenceelectrode can also be formed as a common electrode. In one embodiment,they are formed as a common electrode whose area is greater than thearea of the at least one working electrode. The prior art disclosesexamples for the use of electrode materials for electrochemicalmeasurement methods. Thus, by way of example, electrodes can be coatedwith enzymes or other chemical adjuvants which are specific to theanalyte to be detected. By way of example, for detecting glucose it ispossible to use glucose oxidase (GOD) which converts glucose intogluconolactone. The charge carriers released in the process aredetected. In order to enable this detection, the overvoltage-reducingmaterials are used, which serve as it were as “charge mediators” betweenthe medium and the electrodes.

Many of said overvoltage-reducing materials are harmful to health,however. In particular, these so-called mediators have proved to betoxic, such that it is necessary to immobilize said overvoltage-reducingmaterials for use in implantable sensors in many cases. By way ofexample, a covalent bonding to the electrode and/or a layer of theelectrode, for example a metal layer, can be effected for immobilizationpurposes. In particular, this technique can be used for immobilizingmediators. A second possibility comprises integrating theovervoltage-reducing material into an insoluble layer that is insolublein the fluid, in particular the body fluid, surrounding the implantablesensor in the implanted state. This can be effected for example whenusing manganese dioxide, which is applied as a paste to the electrodeand is then insoluble after drying.

Nitrosoanilines, hexacyanoferrate, ferrocenes or other known mediatorscan be used, for example, as mediators. Other materials can also be usedbesides manganese dioxide.

Besides the described configuration of the at least one workingelectrode, the at least one reference electrode and/or the at least onecounter electrode can also be configured in various ways. In embodimentscomprising at least a reference electrode, the reference electrodeshould comprise an electron system with an electrochemical potentialthat does not change, or changes only insignificantly, in a workingrange of the implantable sensor. Thus, by way of example, given atypical voltage loading (that is to say a voltage between workingelectrode and reference electrode) of typically about 300-500millivolts, e.g. about 450 millivolts, the electrochemical potential ofthe at least one, reference electrode should typically change by notmore than about 1 millivolt. In one embodiment, the electrochemicalpotential of the at least one reference electrode changes by not morethan about 1 microvolt. This stability ensures that the referenceelectrode acts as an actual reference with the potential of which theelectrochemical potential of the at least one working electrode can becompared.

In principle, a multiplicity of materials and/or material combinationscan be used for the reference electrode. A silver/silver chloride(Ag/AgCl) electrode system has proved to be particularly useful in thiscase. Other electrode systems can also be used in principle, but areless common, such as e.g. HgCl₂ electrode systems.

The at least one counter electrode can also be configured in a largenumber of different ways. In this case, however, it should be ensuredthat the at least one counter electrode has an opposite redox behaviorto a redox behavior of the at least one working electrode with respectto the surrounding fluid. Therefore, if an oxidation takes place at theworking electrode, a reduction should take place at the counterelectrode, and vice versa. In principle, pure metals can be used ascounter electrodes, such as platinum for example. This has thedisadvantage, however, that a gas formation, for example a formation ofhydrogen or oxygen, typically occurs at metal electrodes of this type. Agas formation of this type is undesirable, however, when the sensor hasbeen implanted in the body tissue. In this respect, it is once againadvantageous here, too, if an electrode system, in particular a redoxelectrode system, is used in which gas formation is avoided. Inparticular, a Ag/AgCl electrode system can again be used here as well.By way of example, AgCl is reduced in this case. It is evident from thisthat the counter electrode is consumed during operation of the sensor.If the counter electrode has been fully consumed, gas formation onceagain often takes place, such that the implantable sensor generally hasa limited lifetime in operation. Accordingly, in one embodiment, the atleast one counter electrode is made considerably larger than the atleast one working electrode in terms of its area.

The way in which the electrodes are applied to the electrode contactlayers can be effected in various ways, depending on the electrodematerial used. If, by way of example, pure metals are used as electrodematerials, then it is possible, for example, to use film methods (e.g.lamination) or wet-chemical methods, physical application methods(physical vapor deposition, PVD, e.g. vapor deposition or sputtering) orelse chemical application methods (chemical vapor deposition, CVD).Manganese dioxide (MnO₂/C) can be applied for example as a coating, forexample as a paste coating. In this case, various coating methods knownto the person skilled in the art can be used, for example screenprinting, blade coating, nozzle coating or the like. In this case, byway of example, an enzyme can already be mixed with the paste, such thatenzyme and manganese dioxide can be applied in one step. As analternative, it is also possible firstly for manganese dioxide to beapplied, whereupon in a subsequent step the enzyme, for example glucoseoxidase (GOD), is e.g. dispensed thereon or applied in anotherwet-chemical step. The other electrodes are also appliedcorrespondingly. Typical electrode layer thicknesses lie in the range ofabout 10 micrometers, but can also extend to the range of a hundred to afew hundred micrometers. Thinner electrode layers may also by used.

According to embodiments of the invention, the implantable sensor and/ora device which contains the implantable sensor can be used for acontinuous determination of a concentration of at least one analyte inthe body tissue and/or a body fluid. In this case, “continuous” can beunderstood for example to mean that analyte concentrations aredetermined over a specific measurement period, for example one week, atregular intervals (e.g. every five minutes or every hour) or elsepermanently, i.e. with a temporal resolution which is only limited bythe temporal resolution of a measuring device.

One problem, however, in the case of a continuous measurement consistsin a possible drift of the device and/or of the sensor over themeasurement period. A continuous measurement is usually effected byfirstly carrying out a reference measurement by means of a“conventional” measurement method (e.g. taking a drop of blood andmeasuring analyte concentration in the drop of blood), said referencemeasurement then being trimmed with the measured value supplied by theimplanted sensor. A measurement then follows over the measurement periodtaking the initial reference measured value as a basis. However, if theproperty of the implantable sensor changes, for example on account of adrift of an electrochemical potential, in particular of theelectrochemical potential of one of the at least one working electrodeand/or of the at least one reference electrode, then this measurement iserroneous and subject to a drift.

It has been shown in practice that in particular the at least onemembrane layer and the electrode material used for the at least oneworking electrode represent critical points with regard to drift. Theuse of a manganese dioxide paste, in particular a manganese dioxidepaste admixed with an enzyme (e.g. glucose oxidase), which is appliedand subsequently dried, has proved to be advantageous in this case sincethis selection minimizes a drift. Moreover, the use of the advantageouspolyurethane membrane described additionally minimizes the drift.

The implantable sensor according to the embodiments of the invention canfurthermore be provided with an insertion tip for inserting theimplantable sensor into the medium, in particular into a fatty tissue(e.g. into an interstitial fatty tissue). In this case, by way ofexample, the topmost skin layer can be penetrated and the sensor can bepushed at least partly under the dermis.

An insertion tip can be configured in various ways. As mentioned aboveand also known from the prior art, it is possible to use canulas, forexample. In particular, however, it is preferred according to theinvention if the sensor itself that is to say for example the layerconstruction itself, has an insertion tip of this type.

The problem with previous sensors, however, is that they are usuallydesigned to be very thin and wide. As a result, the layer constructionflexes upon insertion, such that the force required for inserting thesensor-cannot be transmitted via the sensor and that the latter bendsbeforehand. However, the sensor according to embodiments of theinvention, in which the electrode contact layers are preferably appliedover a large area and do not have to be structured, enables aconstruction having a high aspect ratio. In this case, an aspect ratioshould be understood to mean the ratio between the height and the widthof the insulating carrier substrate and/or of the entire layerconstruction. Thus, by way of example, insulating carrier substratesand/or layer-constructions can be used in which said aspect ratio, whichis referred to hereinafter as k, is at least about 0.3, and in certainother embodiments k is at least about 0.5, and in yet others k is atleast about 0.9.

If it were desired to achieve such aspect ratios with conventionalsensors, in which the electrode contact layers are structured, it wouldbe necessary, since structured electrodes presuppose a large width ofthe insulating carrier substrate, also to use very thick sensors. Thisin turn means a large cross section of the insertion channel of thesensor. The construction according to the invention, in which a highaspect ratio is achieved whilst simultaneously minimizing the insertionarea, avoids this disadvantage.

In one embodiment, the layered construction of the sensor according tothe invention is a stepped layer construction. In this case, at leasttwo insulating carrier substrates should be present, at least two ofsaid insulating carrier substrates forming a step. In other embodiments,the step is formed in the longitudinal extent direction of theimplantable sensor (that is to say in the insertion direction). For thispurpose, by way of example, one of the at least two insulating carriersubstrates can be made shorter than a second one of the insulatingcarrier substrates, whereby a step arises preferably at the tip of thesensor or in the vicinity of the tip. As a result, it is possible forexample to form three electrodes provided in three different layerplanes. By way of example, at least one of said electrodes can beprovided in the plane of the step, in particular at the step itself. Inthis way, the sandwich structure already described above is extendedfurther into the third dimension.

In practice, the particular properties and the particularly simpleproduction, in particular two-layered constructions or the combinationsthereof, have proved worthwhile, in which case, however, the layered,constructions illustrated can be extended, if appropriate, by additionallayers not mentioned below. On the one hand, a stepped layerconstruction is appropriate, in which at least two insulating carriersubstrates form at least one step. On the other hand, alternatively oradditionally, a so-called “back-to-back” construction can be used, inwhich at least two electrodes are arranged on opposite sides of the atleast one carrier substrate and have oppositely directed electrode areasfacing the medium.

In particular, the stepped construction can be configured in such a waythat at least one electrode is arranged in the plane of the at least onestep, and that the at least one electrode arranged in the plane of theat least one step and at least one further electrode have parallel,equidirectional electrode areas. Furthermore, two steps can be provided,equidirectional electrodes being provided in the two planes of the twosteps. In this case, “equidirectional” should be understood to mean thatthe electrode areas, that is to say the areas facing the medium, pointin the same direction.

The stepped construction can be combined with a “back-to-back”construction in such a way that in addition to the step constructiondescribed in one of the configurations described, at least one furtherelectrode is provided which is arranged on a side of the at least onecarrier substrate that is remote from the at least one step, and isoriented with its electrode area opposite to the step.

The back-to-back construction can be realized, by itself or incombination, for example by providing at least one carrier substrateembedded between a first electrode contact layer and a second electrodecontact layer. It is then possible for at least one first electrode tobe provided on that side of the first electrode contact layer which isremote from the at least one carrier substrate, and for at least onesecond electrode to be provided on that side of the second electrodecontact layer which is remote from the carrier substrate.

A device for determining a concentration of at least one analyte in amedium, in particular a body tissue and/or a body fluid, is furthermoreproposed. The device according to one embodiment of the inventioncomprises at least one implantable sensor in accordance with the abovedescription of the possible configurations. Furthermore, the at leastone device comprises at least one voltage measuring device for measuringa voltage between the at least one working electrode and the at leastone reference electrode. At least one current measuring device formeasuring a current between the at least one counter electrode and theat least one working electrode can furthermore be provided. In addition,the device can furthermore comprise a control device configured forcontrolling the current between the at least one counter electrode andthe at least one working electrode in such a way that the voltagemeasured between the at least one working electrode and the at least onereference electrode is generally equal to a predetermined desiredvoltage. Further methods and devices for determining an electrochemicalpotential difference between the at least one working electrode and theat least one counter electrode and also a concrete electronicconfiguration of circuits of this type are known to the person skilledin the art.

The sensor according to the embodiments of the present inventiondescribed can be used for example for a continuous determination of aconcentration of at least one analyte in the body tissue and/or a bodyfluid. For this purpose, by way of example, the sensor according to theinvention can be implanted, e.g. as part of the device according to theinvention in one of the configurations described, by insertion into thebody tissue. The sensor can then be afforded a certain time within whichan (at least approximate) equilibrium is established in the region ofthe sensor and the surrounding body tissue. By way of example, aswelling of individual or all layers of the sensor may take place duringthis time, which may last e.g. one hour. The patient can subsequentlycarry out a calibration measurement in which, as described above, ananalyte concentration in the body fluid, for example a glucoseconcentration in a drop of blood, is determined by means of aconventional method. The data determined in this case are communicatedto the device according to the embodiments of the invention, for exampleby manual inputting or else by electronic data transfer (e.g. by meansof a cable or a wireless connection). As a result, a calibration pointis made available to the device, and the device according to theembodiments of the invention can trim the measured values input relativeto measured values supplied by the implanted sensor. Afterwards, theimplanted sensor and the device according to the embodiments of theinvention can be used for example over a period of one week, ameasurement being effected for example every five minutes or else inuninterrupted fashion (see above). The measured values determined by thedevice according to the embodiments of the invention can be output tothe patient, for example, or they can also be made available to othersystems, for example medication systems. Thus, by way of example, thedevice according to the embodiments of the invention can be connecteddirectly to an insulin pump that adapts an insulin dose to the bloodglucose concentrations measured. After the measurement time has elapsed,the entire device can be exchanged, or else just the sensor according tothe invention can be exchanged for a new, unspent sensor.

A method for producing an implantable sensor, in particular animplantable sensor in accordance with the above description, which issuitable for determining an analytic concentration in a medium, inparticular in body tissue and/or a body fluid, is furthermore proposed.In one embodiment, the method comprises the steps described below, inwhich case the steps do not necessarily have to be carried out in thefollowing order given. Moreover, various method steps can be repeated orcarried out in parallel, and additional method steps not presented canbe carried out.

In one embodiment of the method, a layered construction is produced, thelayered construction comprising two electrode contact layers, such astwo metal layers, which are applied over a large area in at least twodifferent layer planes to at least one carrier film comprising at leastone insulating material. By way of example, the materials describedabove can be used for the metal layers and the at least one carrierfilm. Furthermore, at least two electrodes are applied to the at leasttwo electrode contact layers, it being possible once again to use thematerials described above. The layered construction is subsequently cutinto sensor strips, such as by means of a precision cutting method.

In contrast to the prior art, therefore, in the method according to theinvention, electrode contact layers are applied over a large area and inat least two different layer planes. An additional structuring of the atleast two electrode contact layers is typically not effected. Complexlithographic structuring methods can be avoided in this case. Theelectrode contact layers and thus also the electrodes are neverthelesselectrically isolated from one another because they are arranged indifferent layer planes.

Furthermore, in the cutting step it is possible to use precision cuttingmethods that have been perfected in the art in the meantime, with cutwidths (i.e. minimum width of the strips produced by the precisioncutting method) of preferably less than 1 mm. In contrast to the priorart, however, these cutting methods now do not have to be oriented tothe already structured electrode layers, which was necessary in methodswhich are known from the prior art and in which the electrodes aregenerally structured lithographically. Thus, in conventional methods, itwas necessary firstly to effect a structuring of the electrodes,followed by a precision orientation of a cutting tool to the alreadystructured electrodes, followed by a cutting method. In the methodclaimed here, however, this initial orientation can be omitted since thefirst cut does not have to be positioned, or only has to be positionedinsignificantly, on account of the electrode contact layers structuredover a large area.

Various layer technologies can be used in the method according to theinvention. Thus, by way of example, it is possible to use laminationmethods, in particular for the layer-by-layer application of the carrierfilms, of metal layers and/or insulator layers (e.g. adhesive films).Various lamination methods are known to the person skilled in the art.In this case, it is also possible to use reel-to-reel film methods.Furthermore, in particular for the application of organic thin films ormetallic thin films, it is also possible to use physical methods (e.g.physical vapor deposition, PVD) and/or chemical methods (chemical vapordeposition, CVD) and/or wet-chemical coating methods. In particular thereel-to-reel film methods described ensure that the method according tothe invention, in particular for producing the implantable sensoraccording to the invention, is extremely cost-effective and reliable incomparison with methods known in the prior art. Carrier films, metallicfilms, organic layers and/or insulator layers can be applied in thisway. In particular, the two particularly preferred layer constructionsdescribed above with one carrier film or two carrier films (stepconstruction) can also be realized by means of the method according tothe invention in this way.

The implantable sensor according to the embodiments of the invention,the device, the use and the production method according to the inventionin one of the configurations described afford a series of advantages,which have already been described in part, over devices and methodsknown from the prior art. In particular, it is possible to realize ageometrical arrangement on two opposite sides (front and rear sides) ofan insulating carrier substrate, e.g. of an insulating carrier substratecomposed of plastic. By virtue of new cutting methods with a reduced cutwidth, it is possible to apply the electrode spacings with an order ofmagnitude comparable to that in the case of an arrangement of a planararea. The electrochemical behavior of the sensors according to theinvention is accordingly not adversely influenced by the arrangement onthe front and rear sides of a substrate.

Furthermore, the production method described is extremely cost-effectiveand can dispense with complex lithographic structuring methods or laserablation. The electrode areas are defined solely by cutting andlamination processes, and continuous, cost-effective manufacturingmethods can be used.

A complicated positioning method for positioning the individualelectrodes can be dispensed with. This is advantageous particularly inthe case of miniaturized sensors (with a resultant small, that is to sayless painful insertion channel) having widths of less than 1 millimeter.Furthermore, the sensors described can be used both in physiologicalsolutions with a high electrolyte content and in: solutions with a lowelectrolyte content.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description of the embodiments of the presentinvention can be best understood when read in conjunction with thefollowing drawings, where like structure is indicated with likereference numerals and in which:

FIG. 1 shows a perspective schematic illustration of a first exemplaryembodiment of an implantable sensor according to the invention;

FIG. 2 shows a second exemplary embodiment of a sensor according to theinvention;

FIG. 3A shows a schematic illustration of an embodiment of a deviceaccording to the invention for determining a concentration of at leastone analyte using a sensor in accordance with FIG. 1;

FIG. 3B shows a schematic illustration of a second exemplary embodimentof a device for determining an analyte using a sensor in accordance withFIG. 2;

FIG. 4 shows a schematic flowchart of a production method for producinga sensor in accordance with FIG. 1;

FIG. 5 shows a schematic flowchart of a production method for producinga sensor in accordance with FIG. 2;

FIG. 6 shows a third exemplary embodiment of an implantable sensor witha step arrangement and a common electrode;

FIG. 7 shows a fourth exemplary embodiment of an implantable sensor withtwo steps and three electrodes; and

FIG. 8 shows a fifth exemplary embodiment of an implantable sensor withone step and three separate electrodes.

In order that the present invention may be more readily understood,reference is made to the following detailed descriptions and examples,which are intended to illustrate the present invention, but not limitthe scope thereof.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE PRESENT INVENTION

The following descriptions of the embodiments are merely exemplary innature and are in no way intended to limit the present invention or itsapplication or uses.

FIG. 1 illustrates a first exemplary embodiment of an implantable sensor110 according to the invention for determining a glucose concentrationin a body fluid. The implantable sensor 110 has an insulating carriersubstrate 112, which may comprise a non-conductive polyester. Theinsulating carrier substrate 112 has a height H of typically about 0.8to about 1 millimeter, but other heights are also possible, in thegeneral range of between about 0.2 and about 2 millimeters. In oneembodiment, the insulating carrier substrate 112 has a width B in theregion of about 1 millimeter. Consequently, an aspect ratio H/B (alsorepresented as “k”) of approximately 0.8 results in this exemplaryembodiment. In other embodiments, other widths B are also possible, suchas widths of between about 0.3 millimeter and about 2 millimeters. Inyet other embodiments, the aspect ratio is selected to be in the regionof about 1.0, and in other embodiments it is selected to be at leastabout 0.3, in which case the reciprocal aspect ratio (that is to say1/k) should also be at least (0.3. This extent of the aspect ratioensures a high stability of the implantable sensor 110.

The insulating carrier substrate 112 is coated on one side with a firstelectrode contact layer 114 and a second electrode contact layer 116arranged on the opposite side. This may involve for example a film orsome other layer of a metal, such as gold, silver, platinum and/oraluminum, for example, which is laminated for example onto theinsulating carrier substrate 112. The electrode contact layers 114, 116are applied to the insulating carrier substrate 112 over a large area.As shown, they extend substantially over the width B of the insulatingcarrier substrate 112.

A respective insulator layer 118, 120 in the form of a film layer, whichin one embodiment is self-adhesive, is applied to the electrode contactlayers 114, 116. Said insulator layers 118, 120 end at the left-hand endof the implantable sensor 110 in FIG. 1 before the end of the insulatingcarrier substrate 112, in such a way that the first electrode contactlayer 114 and the second electrode contact layer 116 are uncovered inthis region and form electrical contacts 122, 124. Electrical contactcan be made with the electrode contact layers 114, 116 via saidelectrical contacts 122, 124, for example by spring contacts beingapplied to said electrical contacts 122, 124, or by means of othercontact means, for example electrical terminals or the like.

According to one embodiment, approximately 1 to 2-centimeters away fromthe electrical contacts 122, 124, the insulator layers 118, 120 haveopenings 126, 128. In the embodiment of FIG. 1, the upper opening 128 isconfigured in the form of a window, whereas the lower opening 126: isconfigured: in such a way that the insulator layer 118 ends here. Otherconfigurations of the openings 126, 128 are also conceivable here. Inthe region of said openings 126, 128, a first electrode system 130 isintroduced into the opening 126 and a second electrode system 132 isintroduced into the opening 128, in such a way that said electrodesystems 130, 132 bear on or are otherwise supported by the electrodecontact layers 114, 116. In these regions, therefore, the electrodesystems 130, 132 together with the electrode contact layers 114, 116form a first electrode 134 and a second electrode 136. In this case, inthe exemplary embodiment illustrated here, the first electrode system130 comprises a Ag/AgCl coating, whereas the second electrode system 132comprises a MnO₂/C (manganese dioxide) layer, mixed with an enzyme suchas glucose oxidase (GOD).

In this exemplary embodiment, the first electrode 134 functions as acommon electrode 138 and realizes the functions of counter electrode 140and reference electrode 142. The second electrode 136 acts as a workingelectrode 144 in this exemplary embodiment.

In the embodiment shown in FIG. 1, the implantable sensor isencapsulated with a membrane layer 146 composed of polyurethane in theregion of the electrodes 134, 136. In this exemplary embodiment, saidmembrane layer 146 is impermeable to the enzyme glucose oxidase, but isat least partly permeable to glucose, in which case, by way of example,diffusion of glucose can, be inhibited by the membrane layer 146.Electrical current limiting, for example, can be realized by means ofthis diffusion-inhibiting effect.

In other embodiments, a layered construction could also be realized inwhich only the working electrode 144, but not the counter electrode 140and/or the reference electrode 142 are covered with theglucose-diffusion-inhibiting membrane layer 146. The advantage of suchan arrangement in which only the working electrode 144 is covered withthe membrane layer 146 is that this arrangement has a lower electricalresistance between the electrodes 140 and respectively 142 and thesurrounding electrolyte. Particularly in the case of the referenceelectrode 142, this reduced electrical resistance becomes apparent byvirtue of an increased interference immunity with respect to externalelectrical influences.

In yet other embodiments, different membrane layers 146 can be used forthe electrodes 144, 142 and 140, or membrane layers which are composed,of a plurality of individual layers having a different functionality.Thus, by way of example, firstly the working electrode 144 could becoated with a membrane layer 146 having diffusion-inhibiting propertiesfor glucose and an impermeability to glucose oxidase, whereas thecounter electrode 140 and the reference electrode 142 remain uncoated.Afterwards, the implantable sensor 110 (completely or partly, i.e. forexample in the region of the electrodes 140, 142, 144) could be coatedwith a further membrane layer 146, which has biocompatible propertiesbut no or only reduced diffusion-inhibiting properties and which onlyserves as an outer protective layer. In this case, therefore, themembrane layer 146 would be constructed in two layers in the region ofthe working electrode 144, but only in one layer in the region of thecounter electrode 140 and the reference electrode 142. Furtherpossibilities for the composition of the membrane layer 146 are alsoconceivable.

Furthermore, in accordance with the exemplary embodiment in FIG. 1, aninsertion tip 148 is provided with the implantable sensor 110. Saidinsertion tip 148 can be configured for example in one piece with theinsulating carrier substrate 112, or an insertion tip 148 fittedseparately to the insulating carrier substrate 112 may also be involved.

FIG. 3A schematically-illustrates a device 310 for determining aconcentration of blood glucose using the sensor 110 in accordance withthe exemplary embodiment in FIG. 1. In this case, the sensor 110 issymbolized only symbolically here by indication of the working electrode144 and the common electrode 138. The device 310 has a voltage measuringdevice 312, which can be used to measure an electrochemical potentialdifference (voltage) between the working electrode 144 and the commonelectrode 138. Furthermore; the device 310 has a current measuringdevice 314, which can be used to measure a current flow between theworking electrode 144 and the common electrode 138. Finally, a controldevice 316 is provided, which controls the current flowing betweenworking electrode 144 and common electrode 138 in such a way that thevoltage measured between working electrode 144 and common electrode 138corresponds to a predetermined desired voltage. For this purpose, thecontrol device 316 can have a dedicated voltage source, for example,which is variable. From the necessary settings of this additionalvoltage source of the control device 316, it is then possible to deducefor example the electrochemical potential difference between workingelectrodes 144 and common electrode 138.

The parts of the device 310 can be spatially separate from one another.Thus, the sensor 110 can be implanted for example partly or completelyinto a body tissue, whereas the rest of the device 310 is accommodatedoutside the body tissue, for example on the skin surface or in aseparate device. Corresponding lines then lead from the currentmeasuring device 314 and the voltage measuring device 312 to theelectrical contacts 122, 124 of the sensor 110.

FIG. 4 illustrates an exemplary embodiment of a method according to theinvention for producing a sensor 110 in accordance with the exemplaryembodiment illustrated in FIG. 1. It should be pointed out that othermethods can also be used, however, in order to produce the implantablesensor 110 according to the invention in accordance with theillustration in FIG. 1. Moreover, the method steps illustrated need notnecessarily be carried out in the order indicated.

In method step 410, the electrode contact layers 114, 116 are applied toa carrier film over a large area. The carrier film need not necessarilybe identical with the insulating carrier substrates 112 since saidinsulating carrier substrates 112 are produced from the carrier filmonly by later cutting (see below). In this respect, both electrodecontact layers 114, 116 and carrier film still have a large area afterthis first method step 410 has been carried out, such that a large-area“sandwich” of a carrier film, embedded between two electrode contactlayers 114, 116, arises. Therefore, the electrode contact layers, too,assume their strip form only after the cutting. By way of example, thelayer technologies described above can be used for applying theelectrode contact layers 114, 116, including lamination techniques. Byway of example, it is possible in this case to use metal films typicallyhaving layer thicknesses in the range of a few tens of micrometers.However, depending on the layer technology used, in other embodimentsthinner or thicker layers are also conceivable, for example layerthicknesses in the range of a few tens to a few hundreds of nanometerswhen using a vapor deposition or sputtering method, or layer thicknessesin the region of one hundred micrometers in the case of reel-to-reellamination methods.

In method step 412 in FIG. 4, the insulator layers 118, 120 are applied.In one embodiment, self-adhesive films can be used, which are in turnapplied over a large area to the layered structure produced after step410 was carried out. In order to produce the openings 126, 128, by wayof example said self-adhesive film can be perforated or structured fromthe outset, but a precise positioning is generally not necessary sincethe precise positioning of the openings 126, 128 is non-critical in manycases. Lamination methods of this type are known to the person skilledin the art and can be used in diverse ways. The openings 126, 128 canalso be introduced subsequently, for example by subsequent cutting andstripping away of the insulator layers 118, 120.

In method step 414 of FIG. 4, the first electrode system 130 is applied.In one embodiment, a Ag/AgCl coating is provided, as described above. Inorder to apply a Ag/AgCl layer, e.g. a Ag/AgCl paste formed for exampleby admixing silver and silver chloride particles with a solvent can beintroduced into the opening 126 by means of a printing method (e.g.screen printing, pad printing, stencil printing) and/or some othercoating method (e.g. blade coating, nozzle coating, in particular bymeans of slotted nozzles, roll coating, or the like). In one embodiment,the opening 126 is covered substantially completely. Other printingmethods can also be used. As shown in FIG. 1, for example, the firstelectrode system 130 can overlap the first insulator layer 118, whichdoes not disturb the functionality of the common electrode 138. Aprecise positioning is therefore not necessary. It is even possible forthe first insulator layer 118 to be concomitantly coated over a largeregion.

The second electrode system 132 is subsequently applied in step 416. Inone embodiment, a mixture of manganese dioxide and glucose oxidase isprovided, as described above. The same method as in method step 414 canbe used for application in this case, for example once again a printingmethod and/or some other coating method. Further methods are alsoconceivable. In one embodiment, a paste is once again used which issolid after corresponding drying and is therefore insoluble in thesurrounding body fluid (electrolyte). Instead of a mixture of manganesedioxide and glucose oxidase, it is also possible firstly to use a puremanganese dioxide, paste onto which glucose oxidase, fort example, isthen dispensed after drying.

In method step 418, the hitherto large-area layer construction isproduced by a cutting method, e.g. a precision cutting method, wherebystrips having the width B (cf. FIG. 1) are produced. In one embodiment,these strips have a longitudinal extent parallel to an insertiondirection 150 (cf. FIG. 1). A precise positioning during the precisioncutting perpendicular to said insertion direction 150 is not necessary,in contrast to conventional methods, which use structured electrodes inthe insertion direction 150 between which the cuts have to be positionedexactly.

In method step 420, the insertion tip 148 is formed onto the insulatingcarrier substrates 112, that have then been produced. In one embodiment,insertion tips 148 can be produced by simultaneous melting, and drawing,or it is also possible for corresponding hot forming to be effected. Inother embodiments, separate tips can be formed onto the insulatingcarrier substrates 112, such as by fusion with the insulating carriersubstrates 112. In yet other embodiments, insertion tips 148 comprise anintegrally formed aspect of the substrate 112. Various otherpossibilities are conceivable. In yet other embodiments, this methodstep can be omitted because, as mentioned above, the implantable sensor110 can also be inserted for example into a separate insertion needle.In yet other embodiments, the sensor 110 is provided with its owninsertion tip 148, such that the body fluid (electrolyte) washes freelyaround the electrodes 134, 136.

In method step 422 in FIG. 4, the membrane layer 146 is applied to thesensor 110. In one embodiment, a simple dipping method can be used inwhich the sensor 110 (without membrane layer) is dipped into a solutionor some other liquid containing the membrane material (or a precursorthereof). In other embodiments, a uniform liquid film can optionallyadditionally be produced by spin-coating, which film can subsequently bedried. A drying step is subsequently carried out, in which the membranelayer 146 dries. A precise positioning of the dipping process is notnecessary since it is only necessary to cover the electrodes 134, 136and more extensive coverage of the sensor 110 is unimportant for themeasurement results. As described above, polyurethanes, for example, canbe used as materials for the membrane layer 146. In other embodiments,other methods can be used for application, for example methods in whicha polymerization does not take place until after the dipping and upondrying, or methods such as spraying methods or printing methods. Themembrane materials used should be biocompatible materials, inparticular, that is to say materials which, during the measurementduration (typically one week, in some instances also longer, plus a“safety time”), do not conduct any reactions with the surrounding bodytissue and/or the body fluid or release toxic substances to anappreciable extent.

FIG. 2 illustrates a second exemplary embodiment of an implantablesensor 110 according to the present invention, an insertion tip 148 notbeing illustrated in this exemplary embodiment. The sensor 110 inaccordance with the exemplary embodiment in FIG. 2 has a firstinsulating carrier substrate 210 layered between a first electrodecontact layer 212 and a second electrode contact layer 214. A secondinsulating carrier substrate 216 is adjacent to the second electrodecontact layer 214, but said carrier substrate does not extend over theentire longitudinal extent of the first insulating carrier substrate210. Thus, at the left-hand end of the sensor 110 as shown in FIG. 2(that is to say opposite to the insertion direction 150), a region ofthe second electrode contact layer 214 is left uncovered, such that anelectrical contact for making contact with the second electrode contactlayer 214 is defined there. At the right-hand end as shown in FIG. 2 (ininsertion direction 150), the second insulating carrier substrate 216ends before the first insulating carrier substrate 210, such that a step220 is formed in this region. It should be pointed out here that as analternative, said step 220 can also be formed “towards the bottom”instead of “towards the top” as in FIG. 2, such that overall the layerconstruction can be inverted.

On the side opposite from the first insulating carrier substrate 210,the second insulating carrier substrate 216 is coated with a thirdelectrode contact layer 222. As shown, all the electrode contact layers212, 214, 222 once again extend over substantially the entire width B ofthe sensor 110. The same materials as in the case of FIG. 1 can be used,in principle, as materials for the electrode contact layers 212, 214,222.

As in FIG. 1 as well, the sensor 110 in accordance with FIG. 2 is alsocoated on the outside with insulator layers 118, 120, which in this caseelectrically insulate the first electrode contact layer 212 and thethird electrode contact layer 222 on the outside from the surroundingelectrolyte, in particular the body fluid. Self-adhesive films may onceagain be involved in this case. As in FIG. 1 as well, in the example inaccordance with FIG. 2, too, the insulators 118, 120 end at theleft-hand end of the sensor 110 before the end of the associatedinsulating carrier substrates 210 and 216, respectively, in such a waythat electrical contacts 224, 226 remain free, via which electricalcontact can be made with the electrode contact layers 212 and 222,respectively.

Analogously to the embodiment in FIG. 1, in the exemplary embodiment inaccordance with FIG. 2, openings 228, 230 are provided in the insulatorlayers 118 and 120. Said openings 228, 230, which may be formed forexample once again as “windows” and/or as simple regions of theelectrode contact layers 212, 222 that are exposed, can once again beproduced as early as during the application of the insulator layers 118,120 or can be produced by later structuring.

A first electrode system 232, a second electrode system, 234 and a thirdelectrode system 236 are introduced into the opening 228, applied to thesecond electrode contact layer 214 in the region of the step 220 andintroduced into the opening 230. In one embodiment, a Ag/AgCl layer isused as first electrode system 232 and as second electrode system 234.In other embodiments, a manganese dioxide-GOD layer is provided as thirdelectrode system 232. Together with the associated electrode contactlayers, 212, 214 and 222, said electrode systems 232, 234, 236 thenrespectively form a first electrode 238, a second electrode 240 and athird electrode 242. In this exemplary embodiment, the first electrode238 acts as a counter electrode 140, the second electrode 240 acts asreference electrode 142 and the third electrode 242 acts as a workingelectrode 144. Consequently, in this exemplary embodiment in accordancewith FIG. 2, the three electrodes 238, 240, 242 are all arranged indifferent layer planes of the layered construction. Consequently, theseelectrodes can be made very wide (that is to say over the entire width Bin this case), but are nevertheless reliably isolated from one another.

In one embodiment, the sensor 110 is, encapsulated by a membrane layer146 in the region of the electrodes 238, 240, 242, which membrane layercan be configured analogously to the exemplary embodiment in FIG. 1.

With regard to the layer thickness ratio and the aspect ratio k=H/B, itshould be pointed out in this case that the abovementioned condition isnot necessarily intended to apply to the height of an individualinsulating carrier substrate 210, 216, but rather preferably to theentire thickness of the layer construction illustrated in FIG. 2. Thisarises from the fact that, in order to ensure that the sensor 110 isinserted under a patient's skin as far as possible without any bending,the sensor 110 overall should have an approximately square crosssection.

FIG. 3B illustrates a device 310 for determining a blood glucoseconcentration using a sensor 110 in accordance with the exemplaryembodiment illustrated in FIG. 1. In contrast to the device inaccordance with FIG. 3A, the three electrodes 140, 144, 142 are nowconfigured as separate electrodes. The electrolyte of the body fluidonce again washes around all three electrodes. At the working electrode144, which once again has glucose oxidase, a conversion of glucose intogluconolactone with formation of electrons once again takes place.Therefore, the electrochemical potential of the working electrode 144 isonce again determined by the concentration of the glucose in the bodyfluid.

In one embodiment, the device 310 comprises a voltage measuring device312 for measuring the voltage between working electrode 144 andreference electrode 142 and also a current measuring device 314 formeasuring a current flowing between the counter electrode 140 and theworking electrode 144. In other embodiments, a control device 316 isprovided, which controls the current flowing between counter electrode140 and working electrode 144 in such a way that the voltage betweenworking electrode 144 and reference electrode 142 reaches apredetermined desired value. Generally, the device functions asdescribed with reference to FIG. 3A.

Finally, FIG. 5 illustrates an exemplary embodiment according to theinvention of a production method for the production of a sensor 110 inaccordance with the exemplary embodiment, in FIG. 2. It should onceagain be pointed out, however, that other production methods for theproduction of said sensor 110 can also be used. Moreover, the methodsteps can once again be carried out in a different order, and once againit is also possible to carry out additional method steps that are notdescribed herein.

Instead of a layer-by-layer construction “from the bottom towards thetop”, the method in FIG. 5 is divided into two partial methods in whicha first partial layer construction (partial method 510) and a secondpartial layer construction (partial method 512) are producedindependently of one another. The two partial layer constructions aresubsequently joined together and processed further in the common method514.

In the partial method 510, firstly in step 516, a first carrier film iscoated with the electrode contact layers 212, 214 over a large area. Onone side of the layered construction thus produced, in step 518, theinsulator film 118 is applied to the first electrode contact layer 212,analogously to method step 412 in accordance with FIG. 4, but only onone side.

In step 520, the first electrode system 232 is introduced into theopening 228 in the insulator layer 118 for example by means of themethod described with reference to FIG. 4.

In step 522, the second electrode system 234 is applied to a region ofthe second electrode contact layer 214 in which the step 220 is formedlater. As an alternative, the second electrode system 234 can be appliedfor example only in the context of the common method 514, that is to sayafter the two partial layer constructions have been joined together (seebelow).

After method steps 516 to 522 have been carried out, the first partiallayer construction is finished. A second partial layer construction isproduced in method steps 524 to 528 (in particular independently of theabove method steps, that is to say in parallel, for example). For thispurpose, firstly in method step 524 a second carrier film is coated withthe third electrode contact layer 222 over a large area and on one side.In method step 526, the insulator layer 120 is applied to the thirdelectrode contact layer 222, leaving an opening 230 remaining. For thetechniques and materials of the application of the individual layers,reference should once again be made to the exemplary embodiments inaccordance with the description corresponding to FIG. 4.

In method step 528 of the partial method 512, the third electrode system236 is introduced into the opening 230. This means that the secondpartial method 512 is finished, and the second partial layerconstruction has been produced.

In the common method 514, in method step 530, the second partial layerconstruction composed of the second carrier film, the third electrodecontact layer 222, the insulator layer 120 and the third electrodesystem 236 is applied to the first partial layer construction composedof the insulator layer 118, the first electrode contact layer 212, thefirst carrier film, the second electrode contact layer 214 and the firstelectrode system 232 and the second electrode system 234. By way ofexample, lamination techniques can once again be used for thisapplication.

In subsequent method step 532, cutting once again takes place, in whichthe hitherto large-area layer constructions are cut into strip-typesensors 110. In this case once again, as described above, exactpositioning is not absolutely necessary.

In method step 534, an insertion tip 148 is optionally formed onto thelayer construction, said insertion tip not being represented in theillustration in accordance with FIG. 2. In method step 536, the membranelayer 146 is applied, analogously to method step 422, for example onceagain by means of a dipping method.

The exemplary methods for producing the sensors 110 as illustrated inFIGS. 4 and 5 can be realized well on an industrial scale. Thus,reel-to-reel methods can be used, in particular, for which automaticmachines are available from other areas of technology, such that specialmanufacturing of costly production equipment is not necessary. Themethod is extremely cost-effective and can be conducted with a highyield and high throughput.

FIGS. 6 to 8 illustrate other embodiments of implantable sensors 110according to the present invention. FIG. 6 shows an exemplary embodimentof an implantable sensor 110 illustrated in a step arrangement. Theimplantable sensor 110 once again has a first insulating carriersubstrate 210, on which a first electrode contact layer 610 is applied.By way of example, said first insulating carrier substrate 210 may havea layer thickness of approximately 200 μm. A first electrode contactlayer 610 is applied to said first insulating carrier substrate 210,analogously to the previous exemplary embodiments, in which case a layerof gold or a layer of some other metal or conductive polymer may onceagain be involved. Said first electrode contact layer has a layerthickness of a few μm, for example.

A second insulating carrier substrate 216 is applied to the firstelectrode contact layer 610, and can be configured analogously to thefirst insulating carrier substrate 210. In this case, on the electrodeside, i.e. on the right-hand side in FIG. 6, the second insulatingcarrier substrate 216 does not extend over the entire length of thefirst insulating carrier substrate 210, such that a step 220 arises inthis region. A second electrode contact layer 612 is applied to thesecond insulating carrier substrate 216, and can be configuredanalogously to the first electrode contact layer 610. An insulator layer120, for example an adhesive tape, is once again applied to the secondelectrode contact layer, analogously to the previous exemplaryembodiments. On the electrode side (i.e. once again on the right-handside of the implantable sensor 110 in FIG. 6), said insulator layer 120does not extend over the entire length of the second insulating carriersubstrate 216 and the second electrode contact layer 612, such that onceagain, analogously to the opening 230 in FIG. 2, an opening 614 remains,that is to say a region in which the second electrode contact layer 612is not covered by the insulator layer 120.

In this region of the opening 614, the second electrode contact layer612 is covered with a first electrode system 616, in one embodimentcomprising a MnO₂/C (manganese dioxide) layer mixed with GOD. Overall, aworking electrode 144 is thus formed in the region of the opening 614.

The first electrode contact layer 610, which is not covered by thesecond insulating carrier substrate 216 in the region of the step 220,is covered. In said-region by a second electrode system 618, which canbe configured for example analogously to the first electrode system 130in accordance with the exemplary embodiment in FIG. 1. In oneembodiment, the second electrode system 618 comprises a Ag/AgCl coating.Consequently, a common electrode 138 performing the functions of counterelectrode 140 and reference electrode 142 is formed from the secondelectrode system 618 and the first electrode contact layer 610, in theregion of the step 220. Working electrode 144 and common electrode 138are once again coated by a membrane layer 146, analogously to theprevious exemplary embodiments.

The exemplary embodiment of the implantable sensor 110 in accordancewith FIG. 6 therefore represents a mixed form of the exemplaryembodiments in accordance with FIGS. 1 and 2. On the one hand, a steparrangement in accordance with the exemplary embodiment in FIG. 2 isprovided, in which-both electrodes 144, 138 are arranged parallel andpoint in the same direction with their free electrode areas (upward inthe exemplary embodiment in accordance with FIG. 6). At the same time,the counter electrode 140 and the reference electrode 142 are configuredas a common electrode 138, analogously to the exemplary embodiment inFIG. 1. In, one embodiment, the width B of the implantable sensor 110 inaccordance with the exemplary embodiment in FIG. 6 is approximately 1mm. This results, taking account of the height H of the insulatingcarrier substrate 210 and 216, in an overall height (approximately 2H)to width (b) ratio of about 0.4. In other embodiments, the electrodes144, 138 have a length L of approximately 1 mm.

FIG. 7 illustrates a further exemplary embodiment of an implantablesensor 110, which once again represents a modification of the exemplaryembodiment in accordance with FIG. 2. The implantable sensor 110 inaccordance with FIG. 7 has three insulating carrier substrates 710, 712and 714, the latter once again being covered by associated electrodecontact layers 716, 718 and 720. In this case, the second insulatingcarrier substrate 712 and the second electrode contact layer 718 areonce again applied to the first insulating carrier substrate 710 and thefirst electrode contact layer 716 in such a way that a first opening 722remains and a first step 724 is formed. The third insulating carriersubstrate 714 and the third electrode contact layer 720 are analogouslyapplied to the second insulating carrier substrate 712 and the secondelectrode contact layer 718 in such a way that a second opening 726 isdefined, as well as a second step 728. In addition, an insulator layer120 is once again applied to the third electrode contact layer 720, saidinsulator layer once again not extending completely as far as theelectrode-side end of the third electrode contact layer 720, such that athird opening 730 remains. In the region of the three openings 722, 726and 730, the electrode contact layers 716, 718 and 720 are respectivelycovered with electrode systems 732, 734 and 736. In one embodiment, thefirst electrode system 732 and the third electrode system 736 eachcomprise, Ag/AgCl coatings. In other embodiments, the second electrodesystem 734 comprises a MnO₂/C (manganese dioxide) layer. Accordingly, areference electrode 738, a working electrode 740 and a counter electrode742 are formed in the different layer planes of the “stair structure” inaccordance with FIG. 7. Consequently, the layer construction of theexemplary embodiment of the implantable sensor 110 in accordance withFIG. 7 corresponds, in principle, to the layer construction in FIG. 2,but with the difference that all the electrodes 738, 740, 742 point inone direction with their electrode surfaces. In this case, the workingelectrode 740 is “framed” between the reference electrode 738 and thecounter electrode 742. The electrodes 738, 740, 742 are once againencapsulated by a membrane layer 146. The layer thicknesses of theinsulating carrier substrates 710, 712, 714 correspond to the layerthickness H of the insulating carrier substrate 210 in accordance withFIG. 6. In one embodiment, thickness H is approximately 200 μm. In otherembodiments, the electrode contact layers 716, 718 and 720 have athickness of approximately 50 μm, in the same way as the electrodesystems 732, 734 and 736. In yet other embodiments, the length L of theindividual openings 722, 726 and 730 is approximately 1 mm.

FIG. 8 illustrates a further exemplary embodiment of an implantablesensor 110, which combines properties of the implantable sensors inaccordance with the exemplary embodiments in FIGS. 6 and 7. Thus, twoinsulating carrier substrates 810 and 812 are once again provided,analogously to FIG. 6. In contrast to FIG. 6, however, rather than anindividual electrode contact layer, two electrode contact layers 814 and816 are applied to the first insulating carrier substrate 810, saidelectrode contact layers each taking up approximately half the width Bof the first insulating carrier substrate 810 and extending along thelength of said first insulating carrier substrate 810. This can beeffected in terms of production technology for example by a large-areaelectrode contact layer firstly being applied to the first insulatingcarrier substrate 810 in order subsequently to electrically isolate andmechanically separate this large-area electrode contact layer into thetwo individual electrode contact layers 814 and 816 by means of acutting method or a laser ablation method, for example. As analternative, the two electrode contact layers 814, 816 can also beapplied to the first insulating carrier substrate 810 directly, that isto say in a manner already electrically insulated from one another. Thesecond insulating carrier substrate 812 is once again applied to the twoelectrode contact layers 814, 816 or the first insulating carriersubstrate 810 in such a way that, at the electrode-side end (on theright in FIG. 8), a first opening 818 remains and a step 820 is formed.

A third electrode contact layer 822 is applied to the second insulatingcarrier substrate, said electrode contact layer, analogously to FIG. 6,once again being covered by an insulator layer 120 in such a way that asecond opening 824 remains at the electrode-side end (on the right inFIG. 8).

In the region of the first opening 818, the first electrode contactlayer 814 is covered with a first electrode system 826, and the secondelectrode contact layer 816 is covered with a second electrode system828. In one embodiment, both electrode, systems 826, 828 compriseAg/AgCl coatings. Consequently, a counter electrode 830 and a referenceelectrode 832 are formed which can once again be used for example in adevice 310 in accordance with the exemplary embodiment in FIG. 3B. Inother embodiments, in the second opening 824, a MnO₂/C (manganesedioxide) layer is applied as third electrode system 834 to the thirdelectrode contact layer 822, such that a working electrode 836 is formedhere.

It can thus be established that the exemplary embodiment of theimplantable sensor 110 in accordance with FIG. 8 has, in principle, a“one-step construction” similar to FIG. 6, but a common electrode 136 isnot used. Rather, counter electrodes 830 and reference electrode 832 lieseparately in a plane of the layer construction. Accordingly, a device310 in accordance with FIG. 3B is used as an example, whereas a device310 in accordance with the exemplary embodiment in FIG. 3A could beused, for example, for the exemplary embodiment of the implantablesensor 110. Analogously, the device 310 in accordance with the exemplaryembodiment in FIG. 3B could also be used for the exemplary embodiment inFIG. 7.

Analogously to the exemplary embodiments in FIGS. 6 and 7, in oneembodiment in accordance with FIG. 8 the implantable sensor 110 iscoated completely or partly with a membrane layer 146 in the region ofthe electrodes 830, 832 and 836. What is common to all three exemplaryembodiments in accordance with FIGS. 6 to 8 is that all the electrodeslie parallel, (albeit in different layer planes) and point in the samedirection with their large-area electrode surface.

The features disclosed in the above description, the claims and thedrawings may be important both individually and in any combination withone another for implementing the invention in its various embodiments.

It is noted that terms like “preferably”, “commonly”, and “typically”are not utilized herein to limit the scope of the claimed invention orto imply that certain features are critical, essential, or evenimportant to the structure or function of the claimed invention. Rather,these terms are merely intended to highlight alternative or additionalfeatures that may or may not be utilized in a particular embodiment ofthe present invention.

For the purposes of describing and defining the present invention it isnoted that the term “substantially” is utilized herein to represent theinherent degree of uncertainty that may be attributed to anyquantitative comparison, value, measurement, or other representation.The term “substantially” is also utilized herein to represent the degreeby which, a quantitative representation may vary from a stated referencewithout resulting in a change in the basic function of the subjectmatter at issue.

Having described the present invention in detail and by reference tospecific embodiments thereof, it will be apparent that modification andvariations are possible without departing from the scope of the presentinvention defined in the appended claims. More specifically, althoughsome aspects of the present invention are identified herein as preferredor particularly advantageous, it is contemplated that the presentinvention is not necessarily limited to these preferred aspects of thepresent invention.

1. An implantable sensor for determining a concentration of at least oneanalyte in a body tissue or a body fluid, the implantable sensor havinga layered construction comprising at least one insulating carriersubstrate and at least two electrodes which are arranged in at least twodifferent layer planes of the implantable sensor, are electricallyisolated from one another by the at least one insulating carriersubstrate and have electrode areas, the electrode areas facing themedium when the sensor has been implanted, and being in contact directlyor via a generally analyte-permeable membrane layer with the body tissueor body fluid over a large area and substantially uniformly, theimplantable sensor further comprising at least two electrode contactlayers in electrical contact respectively with the at least twoelectrodes, wherein the at least one insulating carrier substrate has awidth, and the at least two electrodes or the at least two electrodecontact layers extending over substantially the entire width of the atleast one insulating carrier substrate.
 2. The implantable sensoraccording to claim 1 wherein the at least two electrodes comprise atleast one working electrode and at least one further electrodecomprising at least one of a counter electrode and a referenceelectrode, the at least one working electrode and the at least onefurther electrode being arranged in different planes of the layeredconstruction.
 3. The implantable sensor according to claim 2 wherein theat least one further electrode comprises a common electrode comprising acounter electrode and a reference electrode.
 4. The implantable sensoraccording to claim 1 wherein the at least two electrode contact layersare covered at least partly with respect to the body tissue or bodyfluid by at least one insulator layer.
 5. The implantable sensoraccording to claim 4 wherein the at least one insulator layer comprisesa self-adhesive film layer.
 6. The implantable sensor according to claim1 wherein the at least one membrane layer comprises a polyurethane. 7.The implantable sensor according to claim 1 wherein the at least onecarrier substrate is generally analyte-impermeable.
 8. The implantablesensor according to claim 1 wherein the at least one carrier substratecomprises an insulating polymer.
 9. The implantable sensor according toclaim 7 wherein the insulating polymer comprises a polyester.
 10. Theimplantable sensor according to claim 1 further comprising an insertiontip configured for inserting the implantable sensor into the body tissueor body fluid.
 11. The implantable sensor according to claim 10 whereinthe at least one insulating carrier substrate and/or the implantablesensor has a width B and a height H, the ratio H/B or the reciprocalthereof defining an aspect ratio k, the aspect ratio k being at leastabout 0.3.
 12. The implantable sensor according to claim 11 whereinaspect ratio k is at least about 0.5.
 13. The implantable sensoraccording to claim 11 wherein aspect ratio k is at least about 0.9. 14.The implantable sensor according to claim 1 wherein the layeredconstruction, comprises a stepped layer construction comprising at leasttwo insulating carrier substrates forming at least one step.
 15. Theimplantable sensor according to claim 14 wherein one of the at least twoelectrically isolated electrodes is arranged in the plane of the atleast one step, and wherein said one electrode and another of the atleast two electrically isolated electrodes comprise generally parallel,equidirectional electrode areas.
 16. The implantable sensor according toclaim 14, the stepped construction comprising two steps each comprisingequidirectional electrodes arranged in the planes of the respective twosteps.
 17. The implantable sensor according to claim 14 wherein at leastone further electrode is provided which is arranged on a side of the atleast one carrier substrate that is remote from the at least one step,and is oriented with its electrode area opposite to the step.
 18. Theimplantable sensor according to claim 1 wherein at least two electrodesare arranged on opposite sides of the at least one carrier substrate andhave oppositely directed electrode areas facing the body tissue or bodyfluid.
 19. The implantable sensor according to claim 1 wherein aback-to-back construction, having at least one carrier substrateprovided between a first electrode contact layer and a second electrodecontact layer, at least one first electrode being provided on that sideof the first electrode contact layer which is remote from the at leastone carrier substrate, and at least one second electrode being providedon that side of the second electrode contact layer which is remote fromthe carrier substrate.
 20. A device for determining a concentration ofat least one-analyte in a body tissue or a body fluid, comprising atleast one implantable sensor according to claim 2, the further electrodecomprising at least one counter electrode and at least one referenceelectrode, and further comprising at least one voltage measuring devicefor measuring a voltage between the at least one working electrode andthe at least one reference electrode of the implantable sensor.
 21. Thedevice according, to claim 20, further comprising at least one currentmeasuring device for measuring a current between the at least onecounter electrode and the at least one working electrode of theimplantable sensor.
 22. The device according to claim 20 wherein thedevice is configured for continuously determining a concentration of atleast one analyte in the body tissue or body fluid.
 23. A method forproducing an implantable sensor for determining an analyte concentrationin a body tissue or a body fluid, the method comprising the steps of:applying a first metal layer substantially over a first plane of acarrier film and a second metal layer substantially over a second planeof the carrier film, wherein the first and second metal layers comprisefirst and second electrode contact layers and the first and secondplanes are spaced apart on the carrier film, the carrier film comprisingan insulating material; providing first and second electrodes on therespective first and second electrode contact layers; and cutting thecarrier film into a plurality of strips, wherein each strip comprises animplantable sensor.
 24. The method according to claim 23 wherein thefirst and second metal layers are applied according to a method selectedfrom the group consisting of: a lamination method, a reel-to-reel filmmethod, a. PVD method, a CVD method, and a wet-chemical coating method.25. The method according to claim 23, wherein at least one first carrierfilm is coated on both sides with electrode contact layers, at least onefirst electrode system being applied to one of the two electrode contactlayers on the side remote from the carrier film, and at least one secondelectrode system being applied to the other of the two electrode contactlayers on the side remote from the carrier film.
 26. The methodaccording to claim 25 wherein a second carrier film is coated on oneside with a third electrode contact layer, a third electrode systembeing applied to the third electrode contact layer, the second carrierfilm being applied, with the side remote from the third electrodecontact layer, to the first carrier film surrounded on both sides withelectrode contact layers, in such a way that at least one step isformed.
 27. The method according to claim 23 further comprising applyingat least one insulator layer at least partially over each metal layer.